USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer

The biological roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma (PDAC) are not fully explored. Here the authors perform activity based proteomics with a loss of function genetic screen and identify that USP25 promotes PDAC growth and survival through HIF-1 protein stability and transcriptional activity. Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1 alpha transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1 alpha transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1 alpha axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.

Automated summary

This study reveals that the deubiquitinating enzyme USP25 promotes growth and survival of pancreatic ductal adenocarcinoma (PDAC) by stabilizing and regulating the transcriptional activity of HIF-1 protein. PDAC is characterized by a severely hypoxic microenvironment, and inhibition of USP25 impairs HIF-1 activity and induces cell death in the tumor core. The USP25/HIF-1α axis may be a potential therapeutic target for PDAC.